Exosomal telomerase transcripts reprogram the microRNA transcriptome profile of fibroblasts and partially contribute to CAF formation

Abstract

It is now well accepted that cancer cells change their microenvironment from normal to tumor-supportive state to provide sustained tumor growth, metastasis and drug resistance. These processes are partially carried out by exosomes, nano-sized vesicles secreted from cells, shuttled from donor to recipient cells containing a cargo of nucleic acids, proteins and lipids. By transferring biologically active molecules, cancer-derived exosomes may transform microenvironmental cells to become tumor supportive. Telomerase activity is regarded as a hallmark of cancer. We have recently shown that the transcript of human telomerase reverse transcriptase (hTERT), is packaged in cancer cells derived- exosomes. Following the engulfment of the hTERT transcript into fibroblasts, it is translated into a fully active enzyme [after assembly with its RNA component (hTERC) subunit]. Telomerase activity in the recipient, otherwise telomerase negative cells, provides them with a survival advantage. Here we show that exosomal telomerase might play a role in modifying normal fibroblasts into cancer associated fibroblasts (CAFs) by upregulating $$\mathrm{\alpha }$$ α SMA and Vimentin, two CAF markers. We also show that telomerase activity changes the transcriptome of microRNA in these fibroblasts. By ectopically expressing microRNA 342, one of the top identified microRNAs, we show that it may mediate the proliferative phenotype that these cells acquire upon taking-up exosomal hTERT, providing them with a survival advantage.

Hollow fiber bioreactor allows sustained production of immortalized mesenchymal stromal cell-derived extracellular vesicles

“…Moreover, the low expression levels in iMSC-EVs closely resembled those observed in primary MSC cells, diminishing concerns over safety. Other studies, contrarily to our results, reported hTERT mRNA to be highly secreted in EVs obtained using other isolation methods, such as ultracentrifugation of cultured human amniocytes conditioned media [41] , and Jurkat cell lines [42] , as well as precipitation-isolated tumor cells-derived EVs [43,44] . Furthermore, the same studies showed a functional effect on target cells mediated by the transfer of EV-associated hTERT mRNA.…”

Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles

“…Subsequently, these telomerase-positive cells represent a new cell type-nontumor cells with enhanced telomerase activity [119]. A more recent study reported that exosomal telomerase may play a role in modifying normal fibroblasts into cancer-associated fibroblasts by upregulating αSMA and vimentin [68]. As previously mentioned, the interaction of tumor cells with CAFs is mutualistic.…”

“…Directly target the oncosuppressor CSRP2, induction of the ERK and PAK/LIMK/cortactin signaling cascades [117,118] hTERT Enhancement of telomerase activity [119] Upregulations of αSMA and vimentin [68] Tumor-associated macrophages (TAMs)…”

RNAs in tumour‐derived extracellular vesicles and their significance in the tumour microenvironment

“…Downregulation of Thioredoxin interacting protein (TXNIP) by miR‐146a also activates the Wnt pathway in breast cancer cells which supports invasion and metastasis 75 . TDEs‐encapsulated transcript of human telomerase reverse transcriptase contributes to fibroblast activation through increasing α‐SMA and vimentin expression and also via modulation of fibroblast's microRNA transcriptome profile 76 . Transfer of TDE lncRNA Gm26809 to fibroblasts improved proliferation and invasion of melanoma cells via CAFs 77 .…”